Pyridine sulfonic acids as diuretics

ABSTRACT

NEW 4-ARYLAMINO-3-PYRIDINESULFONIC ACIDS, E.G. THOSE OF THE FORMULA   3-(HO3S-),4-(((R)M-PHENYL)-N(-R&#39;&#39;)-),(R&#34;)N-PYRIDINE   R = H, ALKYL, FREE, ESTERIFIED OR ETHERIFIED OH, CF3,NO2, AMINO, FREE OF FUNCTIONALLY CONVERTED CARBOXY OR SULFO; R&#39;&#39; = H. ALKYL OR ACYL; R&#34; = H OR ALKYL; M = 1-3; N = 1 0R 2; THE N-OXIDE, ESTERS AND SALTS THEREOF, AND A PROCESS FOR THEIR PREPARATION, ARE DIURETICS.

United States Patent 3,787,573 PYRIDINE SULFONIC ACIDS AS DIURETICSReuat Herbert Mizzoni, 90 Valley Brook Road, Long Valley, NJ. 07853, andHerbert Morton Blatter, 851 Springfield Ave., Apt. 22M, Summit, NJ.07901 No Drawing. Continuation-impart of application Ser. No. 20,833,Mar. 18, 1970, now Patent No. 3,674,794, which is a continuation-in-partof abandoned application Ser. No. 876,038, Nov. 12, 1969. Thisapplication Aug. 26, 1970, Ser. No. 67,205

Int. Cl. A61k 27/00 US. Cl. 424-263 3 Claims ABSTRACT OF THE DISCLOSURENew 4-arylamino-3-pyridinesulfonic acids, e.g. those of the formula SOaHR=H, alkyl, free, esterified or etherified OH, CF ,NO amino, free offunctionally converted carboxy or sulfo;

n=1 or 2;

the N-oxide, esters and salts thereof, and a process for theirpreparation, are diuretics.

CROSS-REFERENCES TO RELATED APPLICATIONS This is a continuation-in-partof application Ser. No. 20,833, filed Mar. 18, 1970 (now Pat. No.3,674,794), which is a continuation-in-part of application Ser. No.876,038, filed Nov. 12, 1969 (now abandoned).

SUMMARY OF THE INVENTION The present invention concerns and has for itsobject the provision of new 4-arylamino-3-pyridinesulfonic acids andpharmaceutically useful acid or amino derivatives thereof, preferably ofthose corresponding to Formula I,

R 1-III-Ph S 0 3H R DESCRIPTION OF THE PREFERRED EMBODIMENTS In FormulaI, the phenyl radical Ph is unsubstituted or substituted by one or morethan one, preferably by up to three, advantageously one or two, of thesame or different substituents selected from the group consisting oflower alkyl, e.g. methyl, ethyl, nor i-propyl or -buty1; free,etherified or esterified hydroxy or mercapto, such as lower alkoxy orlower alkylmercapto, e.g. methoxy, ethoxy, nor i-propoxy or -butoxy,methylice mercapto or ethylmercapto, lower alkanoyloxy, e.g. acetoxy orpropionyloxy, halogeno, e.g. fluoro, chloro or bromo; trifiuoromethyl,nitro, amino, monoor di-lower alkylarnino or lower alkyleneimino, e.g.monoor dimethylamino or -ethylamino, pyrrolidino or piperidino; free,esterified or amidated carboxy or sulfo, e.g. lower carbalkoxy oralkoxysulfonyl, carbamoyl, sulfamoyl, monoor di-lower alkylcarbamoyl or-sulfamoyl, e.g. carbomethoxy, carbethoxy, methoxysulfonyl, monoordimethylcarbamoyl or -sulfarnoyl. The term lower, referred to above andhereinafter in connection with organic radicals or compoundsrespectively, defines such with up to 7, preferably up to 4, carbonatoms.

Preferred Ph radicals are phenyl, monoor di-(lower alkyl)-phenyl, mono-,dior tri-(lower alkoxy)-phenyl, mono or di-(halo)-phenyl, (halo, loweralkyl)-phenyl, (halo, trifluoromethyl)-phenyl, monoorbis-(trifluoromethyl)-phenyl, (di-lower alkylamino)-phenyl,(carboxy)-phenyl, (lower carbalkoxy)-phenyl or (sulfamoyl)- phenyl.

The alkyl radicals R R and R are preferably such with up to 4 carbonatoms, e.g. those mentioned above, especially methyl.

An acyl radical R is preferably lower alkanoyl or alkenoyl, e. g.acetyl, propionyl, pivaloyl, acryloyl or methacryloyl, or Ph-loweralkanoyl or -alkenoyl, e.g. benzoyl, phenylacetyl or cinnamoyl.

Esters of the acids of Formula I are preferably lower alkyl or (hydroxy,lower alkoxy, amino or Ph)-lower alkyl esters, e.g. the methyl, ethyl,nor i-propyl, 2-(hydroxy, methoxy, amino or dimethylamino)-ethyl orbenzyl esters.

Salts of said acids are preferably those of therapeutically usefulinorganic or organic bases, primarily the alkali metal, alkaline earthmetal, e.g. sodium, potassium, magnesium or calcium salts, or ammoniumsalts from ammonia or amines, such as those of mono-, dior triloweralkylarnines, or tertiary nitrogen bases, such as pyridine, collidine orlutidine. Resulting compounds that contain basic groups, e.g. aminogroups, may also form acid addition salts, preferably such oftherapeutically useful inorganic or organic acids, such as strongmetalloidic acids, for example hydrohalic, e.g. hydrochloric orhydrobromic acid, sulfuric, phosphoric, nitric or perchloric acid;aliphatic or aromatic carboxylic or sulfonic acids, e.g. formic, acetic,propionic, succinic, glycollic, lactic, malic, tartaric, citric,ascorbic, maleic, hydroxymaleic, pyroracemic, phenylacetic, benzoic,4-amino benzoic, anthranilic, 4-hydroxybenzoic, salicylic,4-aminosalicylic, embonic, nicotinic, methanesulfonic, ethanesulfonic,hydroxyethanesulfonic, ethylenesulfonic, halogenbenzenesulfonic,toluenesulfonic, naphthalenesulfonic or sulfanilic acid; methionine,tryptophane, lysine or arginine.

The compounds of the invention exhibit valuable pharmacologicalproperties. Besides antiinflammatory effects, they primarily showdieuretic, natriand chlorieuretic activity with rapid onset of action,high urine but low potassium excreation levels. This can be demonstratedin animal tests using, for example mammals, e.g. rats or dogs, as testobjects. The compounds of the invention can be administered enterally orparenterally, for example orally within a gelatin capsule to dogs, or inthe form of aqueous solutions or suspensions by stomach tube to rats.The oral dosage may range between about 0.1 and 50 mg./kg./ day,preferably between about 0.3 and 10 mg./kg./day, advantageously betweenabout 1 and 5 mg./kg./day. Simultaneously the test animals may receivevarious salt loads enterally or parenterally, for example, variousamounts of subcutaneously applied 0.9% saline, e.g. ml. thereof permedium-sized dog (beagle). Thus, the compounds of the invention cause anincrease in the excretion of urine, which is collected, e.g. at 2 hourintervals, with or without catheterization, and its volume, sodium,potassium and chloride content estimated and compared with that of thesame untreated or saline-treated animals. Said compounds also cause inthe rat paw edema test [Winter et al., Proc. Soc. Exp. Biol. Med., 111,544 (1962)] a slight reduction of the paw edema induced by carrageenin.Accordingly, the compounds of the invention are mild antiphlogistics andpotent diuretics, sodiand chloriuretics, primarily useful in thetreatment or management of edematous water and salt retention, usuallyin connection with heart and kidney diseases or hypertension. They canalso be used as intermediates in the preparation of other valuableproducts, primarily of pharmacologically active compounds.

Particularly useful are those compounds of Formula I in which Ph isphenyl or phenyl substituted by up to three of the same or differentsubstituents selected from the group consisting of lower alkyl, hydroxy,mercapto, lower alkoxy, lower alkylmercapto, lower alkanoyloxy,halogeno, triiluoromethyl, nitro, amino, monoor dilower alkylamino,lower alkyleneimino, carboxy, sulfo, lower carbalkoxy, loweralkyoxysulfanoyl, carbamoyl, sulfamoyl, monoor di-lower alkylcarbamoyl,monoor di-lower alkylsulfamoyl, R is hydrogen, lower alkyl, loweralkanoyl, lower alkenoyl, Ph-lower alkanoyl or Ph-lowe'r alkenoyl, andeach of R and R is hydrogen or lower alkyl, or the N-oxide, a loweralkyl or (hydroxy, lower alkoxy, amino or Ph) -lower alkyl ester, analkali metal, alkaline earth metal or ammonium salt, or atherapeutically useful acid addition salt thereof.

Preferred are those compounds of Formula I in which Ph is phenyl, monoordi-(lower alkyl)-phenyl, mono-, dior tri-(lower alkoxy)phenyl, monoordi-(halogeno)- phenyl, (halogeno, triiluoromethyD-phenyl, monoor bis-(trifluoromethyD-phenyl, (di-lower alkyl-amino)-phenyl, (carboxy)-phenylor (sulfamoyl)-phenyl, R is hydrogen, lower alkyl or alkanoyl and eachof R and R is hydrogen or lower alkyl, as well as those compounds ofFormula I, wherein Ph also is (halogeno, lower alkyl)-phenyl or (lowercarbal-koxy)-phenyl and R R have the meaning given in this paragraph, orthe lower alkyl esters, ammonium, alkali or alkaline earth metal saltsthereof.

Especially valuable are the compounds of Formula I in which Ph isphenyl, monoor dimethylphenyl, mono-, dior trimethoxyphenyl, monoordichlorophenyl (chloro, trifluoromethyl) -phenyl, monoorbis-trilluoromethylphenyl, dimethylaminophenyl, carboxyphenyl orsulfamoylphenyl and each of R R and R is hydrogen, as well as suchcompounds of Formula I, wherein Ph also is monoor difluorophenyl,bromophenyl, (chloro, methyl)- phenyl or carbethoxyphenyl and each of Rand R are also methyl, or the sodium or potassium salt thereof.

Outstanding are the compounds of Formula I in which Ph is phenyl,fluorophenyl, chlorophenyl, bromophenyl or trifluoromethylphenyl andeach of R R and R is hydrogen, or the sodium or potassium salt thereof.

The compounds of the invention are either prepared according to knownmethods or, more advantageously, according to a new method which is alsoa part of the present invention. For example, they are obtained byconverting in a compound of the Formula H S 03H Rs converting anyresulting compound into another compound of the invention.

The group X is, for example, a free or preferably reactively ethen'fiedor esterified hydroxy group, such as lower alkoxy, lower alkanoyloxy orhalogeno, e.g. such mentioned above, advantageously methoxy or chlorine,or above all a nitro group. Functional derivatives of the acid ofFormula II are, for example the above-mentioned esters or theunsubstituted or N-alkylated amides or hydrazides.

The above-mentioned starting material, especially when X is a nitrogroup constituting the novel feature of the present process, isadvantageously reacted with the amine 'R4-NH-Ph, wherein R is hydrogenor lower alkyl, preferably in the absence, but also in the presence ofdiluents, advantageously of those which are inert to the reagents andare solvents thereof, of catalysts, condensing agents and/ or inertatmosphere, at low temperatures, room temperature or elevatedtemperatures, for example, between about 0 and 150, or preferablybetween about 20 and 130, at atmospheric pressure.

In the above reaction the amine reagent is advantageously used inexcess, at least in order to neutralize any generated acid. It may,however, also be used in equivalent amounts and in the presence of othercondensing agents such as inorganic or organic bases, e.g. alkali metalcarbonates or bicarbonates or tertiary nitrogen bases, for exampletri-lower alkylamines, N,N-dimethyl-aniline or pyridine.

Any resulting amide or hydrazine can be hydrolyzed in the usual manner,for example, with the use of a base, e.g. an aqueous alkali or alkalineearth metal hydroxide, or a quaternary ammonium hydroxide. The compoundsof the invention so obtained may be converted into each other accordingto known methods. For example, resulting compounds in which R stands forhydrogen, may be reacted with a reactive ester of a correspondingalcohol, for example that of a hydrohalic or sulfonic acid or with areactive functional derivative of a corresponding acid, such as a halideor anhydride thereof, e.g. acetyl chloride or acetic anhydride.Resulting acyl derivatives or esters may be hydrolyzed, for example withthe use of acidic or alkaline hydrolyzing agents, esters transesterifiedor resulting acids esterified in known manner, i.e. either directly withthe use of lower alkanols and acidic catalysts, or indirectly via theacid halides, which latter can be prepared with the use of thionyl orphosphorus halides, e.g. thionyl chloride or phosphorus pentachloride.Resulting acids can also be salified in the usual manner, i.e. byreaction with corresponding inorganic or organic bases, e.g. alkalimetal or alkaline earth metal hydroxides, carbonates or bicarbonates,ammonia, amines or corresponding ion exchange preparations. Resultingbases may also be converted into acid addition salts by reacting themwith the corresponding free acids or acidic ion exchange'preparations.

These or other salts, for example, the picrates, can also be used forpurification of the bases obtained; the bases are converted into salts,the salts are separated and the bases are liberated from the salts. Inview of the close relationship between the free compounds and thecompounds in the form of their salts, whenever a compound is referred toin this context, a corresponding salt is also intended, provided such ispossible or appropriate under the circumstances. Resulting mixtures ofisomers can be separated into the single isomers by methods inthemselves known, e.g. by fractional distillation, crystallization and/or chromatography.

The invention further includes any variant of the present process inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Mainlythose starting materials should be used in the reactions of theinvention that lead to the formation of those compounds indicated aboveas being especially valuable.

The starting material is known or, if new, may be prepared according tomethods illustrated in the examples herein. Compounds of Formula II,wherein X is nitro, as well as the unsubstituted or N-alkylated amidesor hydrazides of the acids of Formula I, are new and are considered asadditional subject matter of the present invention. The former areprepared from the corresponding 4- aminopyridine-S-sulfonic acids ortheir functional derivatives, by oxidation, preferably with the use ofperoxides, such as hydrogen peroxide or advantageously persulfuric acid,which latter can be generated in situ from sulfuric acid and hydrogenperoxide. Said new sulfonamides or hydrazides exhibit also valuablepharmacological properties, for example antiinflammatory elfects. Theyare ob tained according to the process described above, i.e. by choosingthe appropriate amides or hydrazides derived from the acids of FormulaII.

The pharmacologically active compounds of the invention are useful inthe manufacture of pharmaceutical compositions containing an effectiveamount thereof in conjunction or admixture with excipients suitable foreither enteral or parenteral application. Preferred are tablets andgelatin capsules comprising the active ingredient together with (a)diluents, e.g. lactose, dextrose, sucrose, mannitol, sorbitol, celluloseand/or glycine, (b) lubricants, e.g. silica, talcum, stearic acid, itsmagnesium or calcium salt and/or polyethyleneglycol, for tablets also(c) binders, e.g. magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose and/orpolyvinylpyrrolid-one, if desired, (d) disintegrants, e.g. starches,agar, alginic acid or its sodium salt, enzymes of the binders oreifervescent mixtures and or (e) adsorbents, colorants, fiavlors andsweeteners. Injectable compositions are preferably aqueous isotonicsolutions or suspensions, and suppositories are advantageously fattyemulsions or suspensions. They may be sterilized and/or containadjuvants, such as preserving, stabilizing, wetting or emulsifyingagents, solution promoters, salts for regulating the osmotic pressureand/or buffers. They may also contain other therapeutically valuablesubstances. Said pharmaceutical compositions are prepared according toconventional mixing, granulating or coating mehtods respectively andcontain about 0.1 to 75%, preferably about 1 to 50% of the activeingredient.

The following examples illustrating the invention are not to beconstrued as being limitations thereon. Temperatures are given indegrees centigrade and all parts wherever given are parts by weight.

EXAMPLE 1 SOaNa melting above 300 and showing in the thin-layerchromatogram on silica gel using chloroform-methanol-diethylamine(822:1) as mobile phase an R =7.5 (developed with platinum tetrachlorideand estimated in U.V. light).

In the analogous manner, the sodium4-(2-chlorophenylamino)-3-pyridinesulfonate is obtained from equalamounts of the corresponding starting materials; R 6.0 (same eluent).

EXAMPLE 2.

6 g. 4-nitro-3-pyridinesulfonic acid are added portionwise to 40 m1.3-trifluoromethylaniline while stirring and cooling, to keep thetemperature below 55. The mixture is stirred for 3 hours at undernitrogen, cooled and diluted with diethyl ether. The precipitate formedis filtered off and recrystallized from ethanol, to yield the4-(3-trifluoromethylphenylamino)-3-pyridinesulfonic acid of the formulaSOaH F30 \N melting at 269-270 with decomposition.

1 g. thereof is taken up in the minimum amount of aqueous postassiumcarbonate, the solution washed with diethyl ether, evaporated in vacuoand the residue recrystallized from water, to yield the correspondingpotassium salt showing in the thin-layer chromatogram on silica gel,using chloroform-methanol-diethylamine (7:221), an R -=7 .0.

EXAMPLE 3 7 g. 4-nitro-3-pyridinesulfonic acid are added portionwise to70 ml. 2-chloro-5-trifluoromethylaniline while stirring and cooling. Themixture is stirred under nitrogen at for 4 hours, cooled and dilutedwith diethyl ether. The precipitate formed is filtered oif andrecrystallized from methanol, to yield the4-(2-chloro-5-trifluoromethylphenylamino)-3-pyridinesulfonic acid of theformula --CF3 N showing on silica gel inchloroform-methanol-diethylamine (822:1) an R =8.0.

EXAMPLE 4 4 g. 4-nitro-3-pyridinesulfonic acid are added to 20 g.4-chloro-2-trifluoromethyl-aniline portionwise and the mixture stirredfor 3% hours at -140 under nitrogen. It is cooled, diluted with diethylether, the precipitate formed filtered off and recrystallized frommethanol, to yield the 4-(4-chloro-2-trifluoromethylphenylamino)-3-pyridinesulfonic acid of the formula F 0 S OaH showing on silica gel inchloroform-methanol-diethylamine (8:2:1) an Rf=9.0.

The starting material used in this and the previous examples is preparedas follows: To 216 ml. 30% aqueous hydrogen peroxide, 432 ml.concentrated sulfuric acid are added at -5 to 0 while stirring. After /2hour, the solution of 60 g. 4-amino-3-pyridinesulfonic acid in 300 ml.concentrated sulfuric acid are added dropwise while stirring at 5 to +5.After stirring for 2 hours at 0", the mixture is allowed to stand in alarge Water bath at room temperature for 16 hours. It is poured onto 3kg. ice, filtered and the residue washed with water and isopropanol, toyield the 4-nitro-3-pyridinesulfonic acid melting at 255-255.5 withdecomposition.

7 EXAMPLE The mixture of 5 g, 4-(3-trifiuoromethylphenylamino)-3-(3-trifluoromethylphenylsulfamoyl)-pyridine and 100 ml. 20%hydrochloric acid is refluxed for 2 hours and slowly evaporated. Theresidue is washed with water and recrystallized from ethanol, to yieldthe 4*(3-trifiuoromethylphenylamino)-3-pyridinesulfonic acid melting at269-270 with decomposition; it is identical with that obtained accordingto Example 2.

The starting material is prepared as follows: The mixture of 175.1 g.4-hydr0xy-3-pyridinesulfonic acid, 468 g. phosphorus pentachloride and100 ml. phosphorus oxychloride is refluxed for 6 hours While stirringunder nitrogen. It is evaporated in vacuo, the residue poured onto iceand the mixture extracted with methylene chloride. The extract is washedwith water, dried and evaporated. The residue is taken up in diethylether, the mixture filtered, the filtrate evaporated, the residuedistilled and the fraction boiling at 120-122/ 1 mm. Hg collected, toyield the 4-chloro-3-pyridinesulfonyl chloride.

11 g. thereof are added portionwise to 100 ml. 3-trifluoromethylanilinewhile cooling and the mixture stirred for 12 hours at 150 undernitrogen. It is cooled, filtered, the filtrate diluted with diethylether and the precipitate formed triturated with diethyl ether. It istaken up in isopropanol, reprecipitated with diethyl ether,recrystallized from Z-butanone-diethyl ether and chromatographed onsilica gel using benzene-isopropanol (9:1) as the mobile phase. Theslower moving fraction having R =5.5 is isolated, to yield the4-(3-trifluoromethylphenylamino)-3- (3-trifluoromethylphenylsulfamoyl)-pyridine.

EXAMPLE 6 The mixture of 5 g. 4(3-trifluoromethylphenylamino)-3-pyridinesulfonamide and 100 ml. 20% hydrochloric acid is refluxed for1 hour and slowly evaporated. The residue is washed with water andrecrystallized from ethanol, to yield the4-(3-trifluoromethy1phenylamino)-3-pyridinesulfonic acid melting at269-270 with decomposition; it is identical with the compound obtainedaccording to Example 2.

The starting material is prepared as follows: The solution of 12 g.4-chloro-3-pyridinesulfonyl chloride in the minimum amount of acetone iscooled to 5 and added dropwise to 20 ml. concentrated aqueous ammoniawhile stirring at 5-8". After stirring for /2 hour at 0, it is filtered,the residue washed with acetone and the filtrate again filtered afterstanding in the cold. The filtrate is evaporated in vacuo, the residuerecrystallized from isopropanol and ethanol-diethyl ether, to yield the4-chloro- 3-pyridinesulfonamide.

The mixture of 4 g. thereof and 40 ml. 3-trifluoromethylaniline isstirred for 12 hours at 150 under nitrogen. After cooling, it is dilutedwith diethyl ether, the precipitate formed filtered off andrecrystallized from isopropanol-diethyl ether, to yield the4-(3-trifluoromethylphenylarnino)-3-pyridinesulfonamide hydrochloride.It is taken up in water, the solution neutralized with aqueous sodiumbicarbonate and evaporated in vacuo, to yield the corresponding freebase. The latter can be taken up in the minimum amount of ethanol, thesolution neutralized with 2 N sodium hydroxide, evaporated in vacuo andthe residue recrystallized from ethanol, to yield the correspondingsodium salt having an R =l1.0 on silica gel usingchloroformmethanol-formic acid (45:45:10) as the mobile phase.

EXAMPLE 7 To 60 ml. 3-chloroaniline, 15 g. 4-nitro-3-pyridinesulfonicacid are added during 45 minutes while stirring and cooling with ice.After stirring overnight at room temperature, the mixture is trituratedseveral times with diethyl ethyl, the precipitate formed filered off andwashed with isopropanol and diethyl ether, to yield the 4-(3- melting at283-285".

It is suspended in water, the suspension adjusted to pH=7.9 with 10%aqueous sodium carbonate, the solution washed with diethyl ether andevaporated in vacuo. The residue is triturated with hot methanol, thesolution filtered oil and the filtrate evaporated in vacuo, to yield thecorresponding sodium salt which is, identical with that obtainedaccording to Example 1.

EXAMPLE 8 The mixture of 5-methyl-4-nitro-3-pyridinesulfonic acid and 50ml. 3-trifiuoromethylaniline is stirred for two hours at 110. Aftercooling it is diluted with diethyl ether, filtered and the residuewashed with diethyl ether, isopropanol and again diethyl ether, to yieldthe 5-methyl-4-(3-trifluoromethylphenylamino) 3 pyridinesulfonic acid ofthe formula CFs melting above 320".

It is suspended in water, the pH of the suspension adjusted to 7.9 with10% aqueous sodium carbonate, the resulting solution washed with diethylether and evaporated in vacuo. The residue is taken up in hotisopropanol, the solution filtered and the filtrate evaporated in vacuo,to yield the corresponding sodium salt melting at 319-320".

The starting material is prepared as follows: To the mixture of 53.5 g.concentrated sulfuric acid and 13.4 g. fuming sulfuric acid (iontaining20% sulfur trioxide), 25 g. 4-amino-3-picoline are added portionwisewhile stirring and keeping the temperature at 40-5 0. The mixture isheated to 195 for 20 hours under nitrogen, cooled and triturated withdiethyl ether until the washings become clear. The gummy residue isfurther triturated with isopropanol until crystalline, filtered 01? andwashed with hot isopropanol and diethyl ether, to yield the 4-amino-5-methyl-3-pyridinesulfonic acid, showing in the thinlayer chromatogramon silica gel, using methanol-water (9: 1) as mobile phase, an R 10.0.

15 g. thereof are taken up in 75 ml. concentrated sulfuric acid and thesolution added dropwise to the mixture of 114 ml. concentrated sulfuricacid and 57 ml. 30% aqueous hydrogen peroxide while stirring at -5 to +5The mixture is stirred for half hour at 0 and 24 hours at 20-25". It ispoured onto ice, the precipated formed filtered otf, washed with water,isopropanol and diethyl ether, to yield the 5-methyl-4-nitro-3-pyridinesulfonic acid melting at 268-269 with decomposition.

. EXAMPLE 9 8.0 g. 4-nitro-3-pyridinesulfonic acid are added portionwiseto 45 m1. ethyl 2-aminobenzoate while stirring under nitrogen, whereuponthe mixture is heated to for 2 hours. After cooling, it is diluted withdiethylether, filtered, the residue washed with hot isopropanol anddiethyl ether, to yield the 4-(2-carbethoxyphenylamino)-S-pyridinesulfonic acid.

The mixture of 10 g. thereof and ml. concentrated hydrochloric acid isheated on the steam bath for 2 hours, the precipitate formed filteredofl, suspended in water and the pH of the suspension adjusted to 8.1with aqueous sodium carbonate. It is evaporated in vacuo, the residuetaken up in methanol, the solution filtered and concentrated, to yieldthe disodium 4-(2- carboxyphenylamine)-3-pyridinesulfonate of theformula NaOOC- SOaNa showing on silica gel in chloroform methanol formicacid (7:2:1) an R '=4.0.

EXAMPLE 10 According to the method illustrated by the previous examples,the following compounds of Formula I are prepared from equivalentamounts of the respective starting materials: R =H.

10 afford the 4-(Z-methylthiophenylamino)-3-pyridinesu1fonic acid of theformula CH3S- S 0:11

Salt

gmmmmmmmm 3,5-C12-COHa 2-CHa3-Cl-C5Ha I lI U Ui H lI lF I 3-HOOCC5H4 H2-HS-C5H4 H All chromatograms on silica gel.

No'rE.A= Chloroformmethanol-diethylamiue (8 :2: 1); BChloroform-methanol-formlc acid (9:1 :1); C =Methanol-water (9:1).

EXAMPLE 11 Preparation of 10,000 tablets each containing 50.0 mg.

of the active ingredient:

Formula G. Sodium 4-(3-chlorophenylamino)-3-pyridinesulfonate 500.00Lactose 1,706.00 Corn starch 90.00 Polyethylene glycol 6,000 90.00Talcum powder 90.00 Magnesium stearate 24.00

Purified water, q.s.

Procedure All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 45 ml. water and the suspension added to theboiling solution of the polyethylene glycol in 180 ml. water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm. openings and compressed into tabletsusing concave punches with 7.1 mm. dimaeter, uppers bisected.

Example 12 5 g. 4-nitro-3-pyridinesulfonic acid are added portionwise toml. 3-methylthioaniline while stirring and cooling, to keep thetemperature below The mixture is stirred for 2 hours at room temperatureand diluted with diethyl ether. The precipitate formed is collected on afilter and recrystallized from methanoldiethyl ether to What is claimedis: 1. A pharmaceutical composition comprising a diuretically effectiveamount of a compound of the formula Rr-N-Ph SOaH RI wherein Ph isphenyl, 'monoor dimethylphenyl, mono-, dior trimethoxyphenyl, monoordichlorophenyl, monoor difluorophenyl, bromophenyl, (chloro,methyl)-phenyl, (chloro, trifluoromethyD-phenyl, monoorbistrifluoromethylphenyl, dimethylaminophenyl, carboxyphenyl,carbethoxyphenyl or sulfamoylphenyl; each of R and R is hydrogen ormethyl and R is hydrogen or the sodium or potassium salt thereof and apharmaceutical excipient.

2. A composition as claimed in claim 1, in which formula of theeffective compound Ph is phenyl, fluorophenyl, chlorophenyl, bromophenylor trifluoromethylphenyl and each of R R and R is hydrogen, or thesodium or potassium salt thereof.

3. A composition as claimed in claim 1, in which the effective compoundis the sodium salt of 4-(3-chlor0phenylamino)-3-pyridinesulfonic acid.

References Cited UNITED STATES PATENTS 3,153,047 10/1964 Jucker et 21.260294.8 F 3,674,794 7/ 1972 Mizzoni et al. 260-294.8 R

ALBERT T. MEYERS, Primary Examiner V. D. TURNER, Assistant Examiner US.Cl. X.R. 260-294.8; 424266 mg UNITED STATES PATENT OFFICE- sU5 +9/l3CERTIFICATE OF CORRECTION Patent No. 3,7 7,573 Dated January 2 1974 flnven toflsijfieno Herbert Mizzoni 'et a1 Q I I I I It: is certifiedthat erroreppears in the above-identified patent and that said LettersPatent are hereby oorrected as shown below:

Column 1, line- 5, after "07901" insert assignors to CIBA-GEIGYCorporation, Ards ley, N. Y.

Signed and sealed this 2nd day of July 197 p.

(SEAL) Attest:

EDWARD M.FLETC HE R, J R. c. MARSHALL DANN Attestlng OfflcerCommissioner of Patents

